IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`BAYER INTELLECTUAL
`PROPERTY GMBH, et al.,
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`Plaintiffs,
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`CIVIL ACTION
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`NO. 15-902
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`v.
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`AUROBINDO PHARMA
`LIMITED, et al.,
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`Defendants.
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`Findings of Fact, Conclusions of Law and Verdict
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`STENGEL, C.J.1
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` July 13, 2018
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`I.
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`Introduction
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`This is a consolidated patent infringement action arising under the Hatch-Waxman
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`Act. The plaintiffs, Bayer Intellectual Property GMBH, Bayer Pharma AG, and Janssen
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`Pharmaceuticals, Inc. (collectively “Bayer”) allege infringement of claim 16 of U.S.
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`Patent No. 7,157,456 (the “’456 patent”), which claims the compound rivaroxaban. The
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`parties concede infringement. Defendants, Mylan Pharmaceuticals Inc. and Sigmapharm
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`Laboratories, LLC submit that the patent is invalid as obvious. I held a four-day bench
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`trial beginning on March 5, 2018 through March 9, 2018.2
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`Presently before me are the parties’ proposed findings of fact and conclusions of
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`law. Pursuan t to Federal Rule of Civil Procedure 52(a), having considered the entire
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`1 Chief Judge Lawrence F. Stengel of the Eastern District of Pennsylvania is sitting by
`designation in this case filed in Delaware District Court pursuant to the provisions of 28 U.S.C. §
`292(b), and by Order of Chief Judge D. Brooks Smith of the Third Circuit. (Doc. No. 268.)
`2 The Court was closed due to inclement weather on March 7, 2018.
`1
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`record and the relevant law, I find that the asserted claim of the ’456 patent is not invalid
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`due to obviousness. The findings of fact and conclusions of law are set forth in further
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`detail below.
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`II.
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`Procedural History
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`On October 9, 2015, plaintiffs filed a complaint alleging infringement of the ’456,
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`’860, and ’339 patents. (Doc. No. 1.) Sigmapharm filed its answer on October 30, 2015,
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`alleging that the patents were invalid. (Doc. No. 26.) On January 19, 2016, Mylan filed
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`its answer, also asserting as an affirmative defense that the patents were invalid. (Doc.
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`No. 66.)
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`
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`The parties filed separate stipulations stating that the products that are the subject
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`of defendants’ ANDAs infringe any valid claims of the ’456, ’860, and ’339 patents,
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`including claim 16 of the ’456 patent. (Doc. Nos. 232, 236.) Plaintiffs later notified
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`defendants that, for purposes of narrowing the issues for trial, they would only assert
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`claim 16 of the ’456 patent. (Doc. No. 286 at ¶ 8; Doc. No. 287 at ¶ 15.)
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`
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`Beginning on March 5, 2018, I held a four-day bench trial. The parties submitted
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`post-trial briefing and on April 25, 2018 I heard closing arguments.
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`III. Findings of Fact
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`A. The parties
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`1. The Bayer plaintiffs are corporations organized and existing under the laws of
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`the Federal Republic of Germany. (Doc. No. 286-1, Ex. 6, ¶¶ 6-7.)
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`2. Janssen is a corporation organized and existing under the laws of the
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`Commonwealth of Pennsylvania. (Id. at ¶ 8.)
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`2
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`3. Mylan is a corporation organized and existing under the laws of the State of
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`West Virginia. (Id. at ¶ 18.)
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`4. Sigmapharm is a limited liability company organized and existing under the
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`laws of the Commonwealth of Pennsylvania. (Id. at ¶ 14.)
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`5. Janssen is the holder of approved New Drug Application No. 22406 for
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`Xarelto® (rivaroxaban). (Id. at ¶ 12.)
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`6. Xarelto® is a factor Xa inhibitor which is indicated to (1) reduce the risk of
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`stroke and systemic embolism in patients with nonvalvular atrial fibrillation; (2) for the
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`treatment of deep vein thrombosis (DVT); (3) for the treatment of pulmonary embolism
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`(PE); (4) for the reduction in the risk of recurrence of DVT and/or PE in patients at
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`continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at
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`least 6 months; and (5) for the prophylaxis (prevention) of DVT, which may lead to PE in
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`patients undergoing knee or hip replacement surgery. (Id. at ¶ 10.)
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`B. The patent-in suit
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`7. The ’456 patent is entitled “Substituted Oxazolidinones and Their Use in the
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`Field of Blood Coagulation.” (Id. at ¶ 1.)
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`8. The named investors are Alexander Straub, Thomas Lampe, Jens Pohlmann,
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`Susanne Roehrig, Elisabeth Perzborn, Karl-Heinz Schlemmer, and Joseph Pernerstorfer.
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`(Id.)
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`9. The patent was issued on January 2, 2007, expires on August 28, 2024, and is
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`currently assigned to Bayer Intellectual Property GmbH. (Id. at ¶¶ 1, 2.) The priority date
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`for the patent is December 24, 1999. (3/5/18 a.m. Tr. 33:12-19.)
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`3
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`C. ANDA No. 208546
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`10. Sigmapharm submitted Abbreviated New Drug Application (“ANDA”) No.
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`208546 to the FDA seeking approval of its proposed rivaroxaban tablets under §
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`505(j)(2)(A)(vii)(IV) of the Federal Food, Drug and Cosmetic Act (“Paragraph IV
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`Certification”) that the claims of the ’456 patent and U.S. patent Nos. 7,585,860 (the
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`“’860 patent”) and 7,592,339 (the “’339 patent”) were invalid, unenforceable, and/or will
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`not be infringed by the commercial manufacture, use, or sale of Sigmapharm’s proposed
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`rivaroxaban tablets. (Doc. No. 286-1, Ex. 6, ¶ 16.)
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`11. By letter dated August 31, 2015, Sigmapharm notified plaintiffs that it
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`submitted ANDA No. 208546. (Id. at ¶ 15.)
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`D. ANDA No. 208561
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`12. Mylan submitted ANDA No. 208561 also seeking approval of its proposed
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`rivaroxaban tablets contained in a Paragraph IV Certification that the ’456, ’860, and
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`’339 patents were invalid, unenforceable, and/or would not be infringed by the
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`commercial manufacture, use, or sale of Mylan’s proposed rivaroxaban tablets. (Id. at ¶
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`20.)
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`13. On September 15, 2015, Mylan notified plaintiffs that it submitted ANDA No.
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`208561. (Id. at ¶ 19.)
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`E. Expert Witnesses
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`14. Dr. Steven Brickner, defendants’ medicinal chemistry expert, received a Ph.D.
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`in organic chemistry from Cornell University; worked in the pharmaceutical industry as a
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`medicinal chemist for 27 years, and has another nine years’ experience as a medicinal
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`chemistry consultant and is a named inventor on thirty (30) U.S. Patents and Patent
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`Applications. (Defs. FF. ¶ 12 (citing 3/5/18 a.m. Tr. 9:20-11:11; 12:14-13:7; DTX-
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`1266).) Dr. Brickner is accredited with discovering linezolid. (Id. (citing 3/5/18 a.m. Tr.
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`10:12-11:13).)
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`15. Dr. Spada, plaintiffs’ medicinal chemistry expert, was the medicinal chemistry
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`head of a factor Xa inhibitor program from 1993 through 1999; he is the co-
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`author/inventor on numerous publications and patent applications in the factor Xa space,
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`including the Ewing II article, discussed infra; and was familiar with the factor Xa field
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`in December of 1999 including by reviewing the literature and attending conferences.
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`(Pltffs. FF. ¶ 16 (citing 3/8/18 a.m. Tr. 57:2-59:1; PTX-9).)
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`16. Although both Dr. Spada and Br. Brickner are experienced medicinal chemists,
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`I find that Dr. Spada’s testimony is credible and reliable and it informs my obviousness
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`analysis.3
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`F. The Person of Ordinary Skill in the Art
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`17. The POSA pertaining to the ’456 patent as of December 24, 1999 (the priority
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`date), is defined as follows,
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`A scientist with a Ph.D. in organic chemistry, or an equivalent discipline, with
`approximately seven (7) years of experience with the synthesis of organic
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`3 In reaching my conclusions, I also considered the expert testimony of Dr. Neil Doherty, III and
`Ivan Hofmann on behalf of the defendants. Likewise, I considered the testimony of Dr. George
`Zhanel, Dr. Jeffrey Olin, and Dr. Christopher Vellturo on behalf of plaintiffs. Finally, I
`considered the testimony of all fact witnesses.
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`5
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`compounds; the purification of organic compounds; and designing pharmaceutical
`compounds. The POSA would also understand the general principles of drug
`design and delivery, including pharmacology, pharmacokinetics, metabolism,
`toxicology and formulation, as well as the role of compounds that inhibit the
`enzyme factor Xa and other anticoagulants in the treatment and prevention of
`thromboembolic disorders and the ability to understand work presented by others
`in these fields.
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`(Defs. FF ¶ 22 (citing 3/5/18 a.m. Tr. 34:16-35:20).)4
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`G. Scope and Content of the Prior Art
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`18. As of the priority date, there were 18 companies and hundreds of researchers
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`working in the factor Xa field. (3/8/18 a.m. Tr. 70:5-15.)
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`19. Among the hundreds of articles published in the field, plaintiffs rely on four
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`review articles published in 1999 that summarize the state of the art: Al-Obeidi, Ewing
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`III, Zhu, and Fevig. (Id. at 71:4-9; PTX-3 (Al-Obeidi); PTX-4 (Ewing III); PTX-6 (Zhu);
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`PTX-325A (Fevig).)
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`20. Anticoagulants are compounds that prevent or treat problematic blood clots.5
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`(3/5/18 a.m. Tr. 16:17-23.)
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`21. Anticoagulants work by suppressing either the synthesis or function of various
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`clotting factors. (Id.)
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`22. A factor Xa inhibitor is one such anticoagulant that prevents blood clot
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`4 Plaintiffs submit that the definition also requires experience with factor Xa inhibitors. (Pltffs.
`FF ¶ 4 (citing 3/8/18 a.m. Tr. 66:6-67:4).) Notwithstanding, the parties’ experts agree that the
`invalidity analysis is the same regardless of whether the POSA requires experiences with factor
`Xa. (3/5/18 a.m. Tr. 36:1-4; 3/8/18 p.m. Tr. Part 1 79:10-14.)
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` 5
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` Blood clot formation is a complex series of enzymatic events triggered by an injury to a blood
`vessel. (3/5/18 a.m. Tr. 15: 8-20.) Following an injury to a blood vessel, platelets aggregate at the
`injury site to form a plug, which can develop into a blood clot. (Id. at 15:16-20.) Blood clots
`become problematic when they form in a vessel by blocking blood flow or moving to another
`area of the body, causing fatal consequences. (Id. at 16:2-10.)
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`formation. Factor Xa inhibitors bind to factor Va, which prevents the formation of a
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`prothombinase complex that converts prothrombin to thrombin. (Id. at 20: 10-16.) By
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`preventing the formation of thrombin, there is no thrombin to convert fibrinogen to fibrin.
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`(Id.) Without fibrin, a clot cannot form. (Id.)
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`23. Factor Xa inhibitors have two key binding sites: the S1 and S4 pockets. (Id. at
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`22: 11-16.)
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`24. The portion of the factor Xa inhibitor that interacts with the S1 site is known as
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`the “P1 group,” and the portion that interacts with the S4 pocket is known as the “P4
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`group.” (Pltff. FF. ¶ 20.) The central scaffold is known as the “core.” (Id.)
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`25. The conventional wisdom in December of 1999 was that in order to be a
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`potent factor Xa inhibitor a compound required a basic P1 group and an aromatic or basic
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`P4 group. (3/8/18 a.m. Tr. 60:12-17; 60:22-61:4, 77:25-81:15; see PTX-3 at 949; see also
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`PTX-325A at 89, 93, 95.)
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`26. The conventional wisdom for designing factor Xa inhibitors was based on the
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`knowledge of the structure of S1 and S4 pockets. The S1 pocket was known to contain a
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`negatively charged aspartic acid and the idea was to use a positively charged residue with
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`at least some basicity6 to interact with the negatively charged aspartic acid, like opposite
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`magnetic poles attracting to each other. (3/8/18 a.m. Tr. 77:25-79:4.)
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`6 Defendants argue that the prior art taught that “basic moieties were being replaced with non-
`basic moieties for binding to the S1 site of thrombin inhibitors.” (Defs. FF. ¶ 10). In support of
`this argument, defendants cite Dr. Brickner’s testimony stating,
`The prior art taught that things were changing. Medicinal chemists were learning that you
`no longer needed to have a highly basic group that bound in the S1 site. In fact, removal
`of basic moiety could be accommodated in this site completely.
`7
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`27. The S4 pocket was known to have three aromatic rings with a strong affinity
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`for other aromatic rings, and also had a cation hole. (Id. at 79:5-81:5.) Conventional
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`wisdom taught that “aromatic and/or basic residues were tolerated and important for
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`binding in the P4 pocket.” (Id. 80:13-15.)
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`IV. Conclusions of Law
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`1. Subject matter jurisdiction over this matter is proper pursuant to 28 U.S.C. §§
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`1331, 1338, and 2201.
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`2. “The presumption that all patents are valid is the starting point for any
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`obviousness determination.” Impax Labs., Inc. v. Lannett Holdings Inc., 246 F. Supp. 3d
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`1024, 1035-36 (D. Del. 2017) (citing 35 U.S.C § 282).
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`3. A party challenging a patent based on obviousness bears the burden of
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`demonstrating by clear and convincing evidence that “the differences between the
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`subject matter sought to be patented and the prior art are such that the subject matter as a
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`whole would have been obvious to a person having ordinary skill in the art.” Bayer
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`Pharma AG v. Watson Laboratories, Inc., 183 F.Supp. 3d 579, 584 (D. Del. 2016)
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`(quoting 35 U.S.C. § 103(a)); see Impax Labs., Inc., 246 F. Supp. 3d at 584-85.
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`4. The standard requires “a reasonable expectation of success.” Medichem, S.A. v.
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`Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006) (quoting In re O’Farrell, 853 F.2d
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`894, 903-04 (Fed. Cir. 1988)).
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`(3/5/18 a.m. Tr. 22:18-24.) Defendants fail to reference any prior art demonstrating a shift in the
`conventional wisdom, and I do not find this testimony credible. The overwhelming evidence
`demonstrates that the prior art in December of 1999 taught the use of a basic P1 group and an
`aromatic and/or basic moiety at P4. (3/8/18 a.m. Tr. 60:12-17; 60:22-61:4, 77:25-81:15; see
`PTX-3 at 949; see also PTX-325A at 89, 93, 95.)
`8
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`5. Obviousness is a question of law that requires consideration of four factual
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`inquiries,
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`(1) the scope and content of the prior art; (2) the level of ordinary skill in the art;
`(3) the differences between the claimed subject matter and the prior art; and (4)
`secondary considerations of non-obviousness, such as commercial success, long-
`felt but unsolved need, failure of others, acquiescence of others in the industry that
`the patent is valid, and unexpected results.
`
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`Id. (citing Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966)).
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`6. In the context of chemical compounds, courts acknowledge that this is an
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`“unpredictable art,” but the Federal Circuit has concluded that a “‘finite number of
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`identified, predictable solutions’ or alternatives ‘might support an inference of
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`obviousness.’” Bayer Pharma AG, 183 F. Supp.3d at 585 (citing Eisai Co. Ltd. v. Dr.
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`Reddy’s Labs. Ltd., 533 F.3d 1353, 1359 (Fed. Cir. 2008)).
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`7. To that end, the Federal Circuit announced a two-party test to analyze chemical
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`compounds under the third Graham factor. Otsuka Pharmaceutical Co., Ltd. V. Sandoz,
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`Inc., 678 F.3d 1280, 1291-92 (Fed. Cir. 2012).
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`8. Under this test, a party seeking to invalidate a chemical compound patent for
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`obviousness must, (1) identify a compound that the POSA would have been motivated to
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`select as the “lead” compound; and (2) provide “a reason or motivation to modify a lead
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`compound to make the claimed compound with a reasonable expectation of success.” Id.
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`at 1292; see Bayer Pharma AG, 183 F. Supp. 3d at 585 (citing Bristol-Myers Squibb Co.
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`v. Teva Pharm. USA, Inc., 752 F.3d 967, 973 (Fed. Cir. 2014)).
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`9. I find that the POSA would not have selected linezolid as a lead compound.
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`10. I find that the POSA would not have modified linezolid to obtain rivaroxaban.
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`9
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`11. Therefore, defendants failed to establish a prima facie case of obviousness by clear
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`and convincing evidence.
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`12. “[O]nce a prima facie case of obviousness has been established, the burden
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`then shifts to the applicant to present evidence of secondary considerations of non-
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`obviousness to overcome this prima facie showing.” Bayer Pharma AG, 183 F. Supp. 3d
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`at 589.
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`13. These considerations include “evidence of commercial success, long-felt but
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`unsolved needs, and/or the failure of others.” Id.
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`14. “A plaintiff may also rebut an obviousness contention by demonstrating that there
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`were unexpected results created by the claimed invention, unexpected properties of the
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`claimed invention, licenses showing industry respect for the invention, and/or skepticism
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`of skilled artisans before the invention.” Id. (citing In re Rouffet, 149 F.3d 1350, 1355
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`(Fed. Cir. 1998)).
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`15. These secondary considerations must be taken into account in the obviousness
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`analysis, but they do not control the conclusion. Id. (citing Pfizer, Inc. v. Apotex, Inc.,
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`480 F.3d 1348, 1372 (Fed. Cir. 2007)).
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`16. There is a nexus requirement that must be met between the “merits of the claimed
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`invention and evidence of secondary considerations” in order for the evidence to be given
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`“substantial weight” in the obviousness analysis. Id. (citing Muniauction, Inc. v.
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`Thomson Corp., 532 F.3d 1318, 1327 (Fed. Cir. 2008)) (quoting Ruiz v. A.B. Chance
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`Co., 234 F.3d 654, 668 (Fed. Cir. 2000)). Stated differently, the secondary considerations
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`10
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`“must be commensurate in scope—“coextensive”—with the claimed features of the
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`invention.” Id. (citing Muniauction,532 F.3d at 1327).
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`17. Even if defendants established a prima facie case of obviousness, I find that the
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`secondary considerations weigh in favor of non-obviousness and a nexus exists between
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`the objective indicia of non-obviousness and the claimed invention.
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`18. Therefore, I find that claim 16 of the ’456 patent is not invalid due to obviousness.
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`V.
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`Discussion
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`To invalidate claim 16 of the ’456 patent as obvious, the defendants must
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`demonstrate by clear and convincing evidence that the POSA would have been motivated
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`to select linezolid as a lead compound and also that the POSA would have been
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`motivated to make the necessary structural changes to linezolid to arrive at rivaroxaban.
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`For the reasons discussed in detail below, I find that defendants fail to meet their burden
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`on both elements. I further find that the secondary considerations weigh in favor of non-
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`obviousness.
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`A. The POSA would not have selected linezolid as a lead compound
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`Defendants assert that a POSA would have selected linezolid as a lead compound
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`because (1) it was the most advanced oxazolidinone in Phase III clinical trials; (2)
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`linezolid had an excellent pharmacokinetic profile and more specifically, 100% oral
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`bioavailability; and (3) linezolid possesses structural motifs characteristic of existing
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`factor Xa inhibitors. I find that defendants fail to demonstrate by clear and convincing
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`evidence that the POSA would have selected linezolid as a lead compound.
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`11
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`At the outset, there were attractive lead compounds in the factor Xa field in
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`December of 1999. Dr. Spada identified seven promising lead compounds that all had
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`activity against factor Xa. (PDX-306; 3/8/18 a.m. Tr. 87:18- 89:9.) Three of these
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`compounds7 had anticoagulant activity and “good” oral bioavailability. (PDX-306; 3/8/18
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`a.m. Tr. 87:25- 88:9.) The other four8 were active factor Xa inhibitors that were used as
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`lead compounds in other factor Xa programs prior to December 1999. (PDX-306; 3/8/18
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`a.m. Tr. 89:10-90:19.)
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`Based on the prior art as of December of 1999, I find that the POSA would have
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`selected one of these seven compounds as the lead compound.9 However, even if there
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`was a dearth of attractive lead compounds in the factor Xa field, the defendants fail to
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`7 The three compounds are YM60828, Fevig 77, and ZK807834.
`8 These four compounds are DX9065a, DABE, BABCH, and TPAM.
`9 Defendants argue that the POSA would not have selected any of these compounds because they
`did not have 100% oral bioavailability, they contained a basic benzamidine substituent, and
`because none had reached phase III clinical trials. (Defs. Br. at 12.) These arguments are
`meritless.
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`First, the testimony at trial demonstrated that 100% oral bioavailability was not necessary for a
`factor Xa inhibitor. (3/8/18 p.m. Tr. Part 1 106:17-25 (“The POSA is not striving to achieve a
`hundred percent bioavailability. At the end of the program, one is bringing forward a molecule
`that has efficacy that was sufficient enough to take into the clinical trial . . . irrespective of . . .
`[one] hundred percent bioavailability.”)
`
`Next, I find that the fact that six of these seven compounds contain a benzamidine is not
`inconsistent with conventional wisdom. (PTX-325A; 3/8/18 a.m. Tr. 76:18-81:15.) While there
`was a shift away from the use of a highly basic benzamidine at P1 to a less basic P1 structure,
`this was done to improve oral bioavailability. (3/8/18 a.m. Tr. 94:25-97:3.) However, two of the
`seven compounds (YM60828 and ZK807834) that contained a basic benzamidine also had good
`oral bioavailability. (3/8/18 a.m. Tr. 94:25-97:3.) Therefore, defendants’ argument for using a
`less basic moiety at P1 does not apply to those two compounds.
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`Finally, defendants argue that unlike linezolid, none of Dr. Spada’s proposed lead compounds
`had reached Phase III clinical trials. I find that whether linezolid had reached phase III trials
`would have been irrelevant to the POSA because linezolid had no activity against factor Xa. (Id.
`at 86:19-87:3.)
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`12
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`demonstrate by clear and convincing evidence that the POSA would have selected
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`linezolid.
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`It is well established that a lead compound is “a compound in the prior art that
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`would be the most promising to modify in order to improve upon its . . . activity and
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`obtain a compound with better activity.” Otsuka, 678 F.3d at 1291 (internal citations and
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`quotations omitted). The court in Otsuka explained,
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`In determining whether a chemist would have selected a prior art compound as a
`lead, the analysis is guided by evidence of the compound’s pertinent properties.
`Such properties may include positive attributes such as activity and potency,
`adverse effects such as toxicity, and other relevant characteristics in evidence . . . .
`Absent a reason or motivation based on such prior art evidence, mere structural
`similarity between a prior art compound and the claimed compound does not
`inform the lead compound selection.
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`Id. at 1292.
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`
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`1. A POSA would not select a compound that was the most advanced
`oxazolidinone in antibiotics as a lead compound for factor Xa inhibitors.
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`Defendants argue that the prior art disclosed various anticoagulants including
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`
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`factor Xa inhibitors with oxazolidinones,10 but that the prior art was devoid of a factor Xa
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`inhibitor that had entered clinical trials. (Defs. FF. ¶ 44 (citing 3/6/18 a.m. Tr. 38:7-
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`39:13, 40:8-10).) The fact that linezolid was known as the “most advanced
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`oxazolidinone” and was in Phase III clinical trials in December of 1999, defendants urge,
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`demonstrate that the POSA would have selected linezolid as a lead compound. (Defs. FF.
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`¶¶ 45, 46.)
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`10 “Oxazolidinones are a class of compounds that includes a five-membered ring containing an
`oxygen atom, a carbon atom, and a nitrogen atom, such that the carbon atom between the oxygen
`atom and the nitrogen atom is double-bound to another oxygen atom, also known as a carbonyl
`moiety.” (Defs. FF. ¶ 15.)
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`13
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`At the outset, defendants’ argument is a red herring. Linezolid was the most
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`advanced oxazolidinone antibiotic and it was in Phase III trials for antibiotic indications.
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`The relevant issue here, however, is whether the prior art taught that oxazolidinones were
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`useful in factor Xa inhibitors. It did not. There was no evidence that a factor Xa inhibitor
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`with an oxazolidinone core could have potent activity against factor Xa. (3/8/18 a.m. Tr.
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`63:10-19; 3/8/18 p.m. Tr. 9:9-13.) In fact, the ’092 publication was the only one reference
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`to factor Xa inhibitors with oxazolidinone cores in the prior art.11 This publication
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`discloses compounds with an oxazolidinone core, but it contains no data that these
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`compounds are potent factor Xa inhibitors. (DTX 1080; 3/8/18 p.m. Tr. Part 2 44:24-
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`47:14.) Dr. Bricker did not rely on this reference (3/8/18 p.m. Tr. Part 2 47:14-18), and
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`the POSA would not have relied on it either.
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`Equally unpersuasive is defendants’ argument that the Riedl publication disclosed
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`oxazolidinones for the treatment of thrombosis. (Defs. FF. ¶ 46 (“Riedl teaches that
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`oxazolidinones have non-anti-infective activity, including platelet inhibition activity,
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`which allows oxazolidinones to ‘be useful in the treatment of thrombosis and myocardial
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`infarction.’”).) Riedl does not address factor Xa inhibitors. (See DTX 1265 at 630; 3/8/18
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`a.m. Tr. 106:13-19.) It describes oxazolidinone antiplatelet activity. (See DTX 1265 at
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`630; 3/8/18 a.m. Tr. 107:4-16.) This reference actually teaches away from the selection of
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`linezolid because a factor Xa inhibitor with antiplatelet activity creates an increased risk
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`11 Dr. Brickner also relied on the ’371 publication (DTX-1133) as prior art disclosing
`oxazolidinones in factor Xa inhibitors. However, this reference disclosed oxazolidinones as a
`substituent and not as a core structure. (3/5/18 p.m. Tr. 81:3-15.) A POSA would not be
`motivated to selected linezolid as a lead compound based on this reference.
`14
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`for bleeding. (3/8/18 a.m. Tr. 108:15-20.) I find that the prior art taught away from the
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`selection of linezolid as a lead compound.
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`2. 100% oral bioavailability, by itself, is an insufficient reason to select a lead
`compound.
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`Defendants also assert that a POSA would have selected linezolid because it had
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`100% oral bioavailability. This argument fails for several reasons. First, 100% oral
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`bioavailability is meaningless without activity against factor Xa. Dr. Spada testified,
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`[W]hen one starts with a lead, one starts with a molecule that has some activity
`against the target itself, and in this case we’re talking about Factor Xa. And if I
`could digress . . . I’ve been a medicinal chemist for 33 years, and in my entire
`career, I cannot recall one single example in interactions with my colleagues,
`either in the United States or in other locations, where someone had proposed
`starting a program with a lead that didn’t have activity on the target. It’s just
`simply not the way medicinal chemistry is done.
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`(3/8/18 a.m. Tr. 61:10-21.) I find Dr. Spada’s testimony credible and I conclude that the
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`POSA would not select a lead compound with no known activity against factor Xa.
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`This argument also fails because100% oral bioavailability, without more, is an
`
`insufficient basis for selecting linezolid as a lead compound. Although oral
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`bioavailability was a factor that was considered in selecting a lead compound, a POSA
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`would not need that level of oral bioavailability for a factor Xa inhibitor. In fact, Zhu
`
`teaches that 20 percent oral bioavailability is “good.” (PTX-6; see 3/8/18 a.m. Tr. 101:19-
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`25 (Zhu indicates that “you don’t need 100 percent oral bioavailability and that you can
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`get effective, efficacious compounds with oral bioavailability in the 20 percent range.”).)
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`Indeed there were two compounds that were known in the prior art that had “good” oral
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`
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`15
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`bioavailability.12 Defendants have failed to demonstrate that the POSA would have
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`selected linezolid as a lead compound rather than one of these two compounds.
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`Finally, the prior art taught chemists to address bioavailability by incorporating
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`less basic P1 replacements into factor Xa inhibitors to obtain “good” oral bioavailability.
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`(3/8/18 a.m. Tr. 98:16-99:9, 102:1-6; PTX-325A; PTX-4.) Conventional wisdom did not
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`teach the use of compounds with no activity against the target and 100% oral
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`bioavailability. I find that defendants failed to demonstrate by clear and convincing
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`evidence that the POSA would have selected linezolid because it maintained 100% oral
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`bioavailability.
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`3. Linezolid does not have structural motifs characteristic of factor Xa
`inhibitors.
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`Defendants next argue that linezolid has structural motifs characteristic of factor
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`Xa inhibitors. This argument fails for several reasons. First, Ewing II taught the use of a
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`pyrrolidinone scaffold, which defendants argue is similar to an oxazolidinone scaffold in
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`factor Xa inhibitors. (Def. FF. ¶ 49 (citing 3/5/18 p.m. Tr. 4:24-6:8) (also citing DTX
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`1081 at 3559-60).) However, Ewing II does not teach using an oxazolidinone or linezolid
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`as a lead. (3/8/18 p.m. Tr. Part 3:22-4:18.) What is more, Ewing provided no reason to
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`use an oxazolidinone core instead of a pyrrolidinone. (Id. at 4:19-5:5.) This argument is
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`further weakened by the fact that Ewing actually discloses data for two pyrrolidinone
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`core structures, and the one closer in structure to an oxazolidinone was 40-fold less
`
`
`12 ZK807834 demonstrated oral bioavailability of 20 percent and Fevig 77 demonstrated oral
`bioavailability of 53percent. (PTX-6 at 70, 72-73; PTX-325A at 95.)
`16
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`

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`potent. (Id. at 6:16-9:13.) A POSA simply would not have selected linezolid as a lead
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`based on this prior art.
`
`
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`Next, defendants argue that “Quan teaches that a factor Xa inhibitor containing
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`two six membered rings linked via a single bond, similar to that found in linezolid, would
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`fit into the S4 site of factor Xa.” (Def. FF. ¶ 50 (citing 3/5/18 a.m. Tr. 46:21-47:1; 3/5/18
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`p.m. Tr. at 6:9-22, 7:15-8:25; 3/6/18 a.m. Tr. at 19:3-11; DTX-1129 at 2764).) Quan does
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`not stand for this proposition. Quan teaches the use of two aromatic rings at P4 that
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`happen to be 6-membered rings. (3/8/18 p.m. Tr. Part 1 15:1-14.) The morpholine in
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`linezolid is not aromatic and a POSA would not have selected linezolid as a lead
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`compound based on the ring shape. (Id. at 15:15-16:3.) Defendants submit that “there is
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`no requirement that a factor Xa inhibitor must include an aromatic and/or basic moiety
`
`that can fit into the P4 pocket of the factor Xa active site.” (Defs. Br. at 11 (citing Defs.
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`FF. ¶ 55.) However, this runs contrary to the conventional wisdom which taught the use
`
`of aromatic and/or basic groups at P4, and defendants fail to cite to any prior art that
`
`would convince me otherwise.
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`I find that